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BACKGROUND & AIMS: Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for patients with advanced HB. METHODS: We performed a comprehensive genomic, transcriptomic and epigenomic characterization of 159 clinically annotated samples from 113 patients with HB, using high-throughput technologies. RESULTS: We discovered a widespread epigenetic footprint of HB that includes hyperediting of the tumor suppressor BLCAP concomitant with a genome-wide dysregulation of RNA editing and the overexpression of mainly non-coding genes of the oncogenic 14q32 DLK1-DIO3 locus. By unsupervised analysis, we identified 2 epigenomic clusters (Epi-CA, Epi-CB) with distinct degrees of DNA hypomethylation and CpG island hypermethylation that are associated with the C1/C2/C2B transcriptomic subtypes. Based on these findings, we defined the first molecular risk stratification of HB (MRS-HB), which encompasses 3 main prognostic categories and improves the current clinical risk stratification approach. The MRS-3 category (28%), defined by strong 14q32 locus expression and Epi-CB methylation features, was characterized by CTNNB1 and NFE2L2 mutations, a progenitor-like phenotype and clinical aggressiveness. Finally, we identified choline kinase alpha as a promising therapeutic target for intermediate and high-risk HBs, as its inhibition in HB cell lines and patient-derived xenografts strongly abrogated tumor growth. CONCLUSIONS: These findings provide a detailed insight into the molecular features of HB and could be used to improve current clinical stratification approaches and to develop treatments for patients with HB. LAY SUMMARY: Hepatoblastoma is a rare childhood liver cancer that has been understudied. We have used cutting-edge technologies to expand our molecular knowledge of this cancer. Our biological findings can be used to improve clinical management and pave the way for the development of novel therapies for this cancer.
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Colina Quinasa , Hepatoblastoma , Neoplasias Hepáticas , beta Catenina/genética , Biomarcadores de Tumor/análisis , Proteínas de Unión al Calcio/genética , Colina Quinasa/antagonistas & inhibidores , Colina Quinasa/metabolismo , Metilación de ADN , Descubrimiento de Drogas/métodos , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Hepatoblastoma/genética , Hepatoblastoma/metabolismo , Hepatoblastoma/mortalidad , Hepatoblastoma/patología , Ensayos Analíticos de Alto Rendimiento , Humanos , Lactante , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Proteínas de la Membrana/genética , Proteínas de Neoplasias/genética , Pronóstico , Medición de Riesgo/métodosRESUMEN
We report a 12-day-old male who was admitted with vomiting because of an unusual early complication of Marfan's syndrome (MS): a sliding hiatal hernia. Initial ultrasound showed no stomach at its normal position and the chest X-ray presented an intrathoracic gas bubble with the nasogastric tube inside. An upper gastrointestinal contrast study confirmed the complete herniation of the stomach into the thorax. Via an exploratory laparotomy it was carefully reintroduced into the abdomen, following a hiatal reconstruction. A Thal fundoplication and a gastrostomy were also performed to guarantee its fixation. Although characterized by cardiac/aortic abnormalities, MS should be considered in any infant with hiatal/paraesophageal hernia, which should be repaired early to avoid gastric ischemia/volvulus.
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BACKGROUND: Venous malformations (VMs) can occur in any part of the body; however, the gastrointestinal tract is a frequent location. These are usually asymptomatic, thus, representing a challenge to diagnosis. Intestinal location of VMs can be associated with severe complications that ultimately require an emergency surgery. Our aim was to analyze all patients with an intestinal VM with special focus on those who required emergency surgery. MATERIALS AND METHODS: A retrospective study of patients presenting complication caused by intestinal VM was performed. Clinical records, associated anomalies, physical findings, and treatment were assessed. RESULTS: Twenty-one patients had a diagnosis of intestinal VM, 16 (76%) were associated to blue rubber bleb nevus syndrome (BRBNS) and 5 (24%) were isolated. Only four (19%) of the total cases presented an episode of acute abdomen with hemodynamic instability that required an emergency surgery. Findings included two gastrointestinal bleedings, one volvulus, and one intussusception of small bowel. All patients underwent an uneventful recovery and are presently doing well. CONCLUSION: Intestinal VM can be challenging to diagnose in emergency situations, such as gastrointestinal situation or acute abdomen. The complications associated with it must be kept in mind, regardless of its low incidence.
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Urgencias Médicas , Intestinos/irrigación sanguínea , Malformaciones Vasculares/diagnóstico , Malformaciones Vasculares/cirugía , Venas/anomalías , Niño , Preescolar , Femenino , Neoplasias Gastrointestinales/complicaciones , Humanos , Masculino , Nevo Azul/complicaciones , Estudios Retrospectivos , Neoplasias Cutáneas/complicaciones , Resultado del Tratamiento , Malformaciones Vasculares/complicaciones , Venas/cirugíaRESUMEN
Aim Short bowel syndrome (SBS) is the leading cause of intestinal failure (IF) in the pediatric population. Our aim was to review long-term outcome of ultrashort bowel syndrome (USBS) in an Intestinal Rehabilitation Unit (IRU). Patients and Methods Retrospective study of patients with USBS (defined as < 10 cm of remnant small bowel) treated between 2000 and 2015. Demographic data, clinical, and treatment variables including parenteral nutrition (PN), surgical techniques, and intestinal transplantation (IT) were analyzed. Results Out of 250 children, 30 referred to the IRU met inclusion criteria. Upon first assessment, patients had a median age of 3 (1-217) months and had undergone 3 (1-6) previous laparotomies that left 5 (0-9) cm of remnant small bowel. The main cause of USBS was neonatal midgut volvulus (50%). Follow-up was 28 (4-175) months. Advanced IF-associated liver disease (IFALD) was documented in 63%. None of the patients achieved digestive autonomy and was consequently considered for IT. One patient was excluded, five died before IT, and three are still on the waiting list. Six patients received an isolated IT, 6 a combined liver IT, and 18 a multivisceral graft. Digestive autonomy was achieved in 71% after 31 (14-715) days after IT and currently 62% are alive and off total PN. A significant drop in IFALD progression prior to IT was observed with the introduction of new lipid emulsions in 2010 (SMOF or Soy oil MCT (mid-chain triglycerides) Olive oil Fish oil). Conclusion A multidisciplinary IRU including an IT program offers a comprehensive approach for patients with IF and is crucial to improve survival rate of USBS. New PN lipid emulsions had an impact on IFALD progression and may eventually reduce overall mortality.
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Unidades Hospitalarias , Grupo de Atención al Paciente , Síndrome del Intestino Corto/rehabilitación , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Intestino Delgado/trasplante , Masculino , Nutrición Parenteral Total , Estudios Retrospectivos , Síndrome del Intestino Corto/mortalidad , Síndrome del Intestino Corto/cirugía , España , Resultado del TratamientoRESUMEN
Aim Hepatocellular carcinoma (HCC), although being infrequent, is the second-most common primary hepatic malignancy in children, after hepatoblastoma (HB). The prognosis is very poor. We present our series of children with HCC referred to our transplant unit to be assessed as candidates for liver transplantation (LT). Methods A retrospective review of HCCs referred to our transplant unit in the past 20 years (1994-2015) was performed. Age at diagnosis, disease-free survival, location of recurrence, initial treatment, secondary treatment, and mortality were noted. Main Results Ten patients (8 boys, 2 girls) met the inclusion criteria. Median age at diagnosis was 11.5 years (0.5-14). HCC was associated with tyrosinemia in two patients, while the tumor developed in absence of previous liver disease in eight. Seven children attempted tumor resection earlier elsewhere. LT was not considered suitable in six patients due to extrahepatic tumor extension and finally it was performed in four (two with tyrosinemia and two with "de novo" HCC). Only one of the transplants was primary, and the other three were performed as rescue therapy. After 78 (66-90) months of follow-up, the two patients with tyrosinemia remain alive and disease free, while the other two had distant relapses, 35 and 37 months after LT, respectively, and finally died due to tumor progression. Conclusions HCC is a rare, very aggressive tumor in children who has a very poor prognosis. Our results suggest the need for new strategies. Early referral of all cases to highly specialized centers with a liver transplant unit and perhaps a more liberal use of LT, even for selected, apparently resectable cases, are possible options.
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Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Trasplante de Hígado , Adolescente , Carcinoma Hepatocelular/mortalidad , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Neoplasias Hepáticas/mortalidad , Masculino , Derivación y Consulta , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoAsunto(s)
Antibacterianos/farmacología , Infecciones por Salmonella/microbiología , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/enzimología , Antibacterianos/uso terapéutico , Preescolar , Heces/microbiología , Femenino , Regulación Bacteriana de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Humanos , Infecciones por Salmonella/tratamiento farmacológico , Resistencia betalactámica/genética , beta-Lactamasas/genética , beta-Lactamasas/metabolismoRESUMEN
AIM: The ideal repair of esophageal atresia (EA) is primary anastomosis with closure of the fistula if present. Long gap or local circumstances prompt other procedures that occasionally lead to disastrous complications. The aim of this study was to analyze the management of these complications in a tertiary referral center. PATIENTS AND METHODS: A retrospective review of patients treated for EA between 1993 and 2013 was conducted. Both the patients were primarily treated by us, and referrals from elsewhere after two or more failed operations were included. RESULTS: In total, 23 patients were included (3/176 cases of EA treated primarily by us and 20 referrals). Of the 23 patients, 6 had type I EA, 15 type III (four long gaps), 1 type IV, and 1 type V. Cardiac anomalies were associated in seven cases, duodenal atresia in three, and Down syndrome in two patients. Primary anastomosis was initially achieved in 12 patients. Primary or secondary Foker lengthening was used in seven cases. The causes of the failure were anastomotic leaks in nine, unmanageable strictures in seven, and refistulization in five patients. These patients required 66 reoperations (median of 3 [2-7]) before inclusion in the study. Radical tertiary treatment consisted of 15 esophageal replacements (11 colonic grafts and 4 gastric pull-ups), and 1 esophageal-gastric disconnection. Five patients previously treated with esophageal replacement and referred for graft problems required 13 interventions. Two families did not give consent for one replacement and one disconnection. Complications appeared in 12 patients, and 9 additional operations were required in 7 patients. With a follow-up of 31 months (range, 4-139 months) 15 patients take all their meals per os, 5 occasionally use the gastrostomy, and 2 and 1 are fed exclusively via gastrostomy or jejunostomy. All tracheoesophageal fistulas were closed, but 15 cases are below p3 for weight and 12 for height. Three patients (13%) ultimately died 32 months (range, 9-56 months) after the first operation (due to aspiration in one, and for causes unrelated to it in the other two [tracheostomy obstruction and Guillain-Barré syndrome]). CONCLUSIONS: When repeated complications appear after EA repair, radical surgical attitudes may be justified. If esophageal continuity cannot be reestablished, the native esophagus may have to be discarded and replaced. Many complications should be expected, but the end result can be good. These patients should be referred to centers with large experience in the management of this complex condition.
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Atresia Esofágica/cirugía , Esofagoplastia/métodos , Complicaciones Posoperatorias/cirugía , Niño , Preescolar , Atresia Esofágica/mortalidad , Esófago/cirugía , Femenino , Gastrostomía , Humanos , Lactante , Masculino , Complicaciones Posoperatorias/mortalidad , Reoperación , Estudios Retrospectivos , Estómago/cirugía , Centros de Atención Terciaria , Resultado del TratamientoRESUMEN
INTRODUCTION: Severe tracheobronchial injuries (TBI) in children are usually traumatic or iatrogenic. However, they can also be caused by mediastinal infections that lead to critical situations. We herein report our experience in the treatment of these lesions. METHODS: A retrospective study was conducted for patients treated at our center from 2008 to 2014. TBI was diagnosed by imaging studies and bronchoscopy. Treatment was initially conservative (drainage of air and secretions, mechanical ventilation with minimal pressures, and an early extubation) with a limited use of surgical procedures whenever necessary. RESULTS: A total of 10 patients (7 males and 3 females) with a median age of 7.5 years (range, 3-17 years) suffered TBI. The mechanism was traumatic in six (three accidental and three iatrogenic) and mediastinal infection in four (three mycotic and one bacterial abscesses). All traumatic cases responded to conservative measures, except one iatrogenic lesion, which was surgically repaired. There were no complications or residual damages. Two patients with mediastinal infection presented with sudden cardiorespiratory arrest, one with hemoptysis caused by an arteriotracheal fistula and the other because of carinal rupture. Both died before any therapeutic measures could be taken. The other two patients were treated, one with previous extracorporeal membrane oxygenation support, underwent arterial embolization, but ultimately died, and the other one survived, but required esophagectomy and creation of a thoracostome for secondary wound closure of the bronchocutaneous fistula. CONCLUSION: Conservative treatment with gentle respiratory support suffices in most traumatic cases of TBI. Infectious abscesses with involvement of adjacent structures sometimes require complex surgery and are life-threatening.
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Bronquios/lesiones , Lesión Pulmonar/terapia , Traumatismos del Cuello/terapia , Tráquea/lesiones , Adolescente , Bronquios/cirugía , Broncoscopía , Niño , Preescolar , Terapia Combinada , Drenaje , Femenino , Humanos , Intubación Intratraqueal , Lesión Pulmonar/diagnóstico , Lesión Pulmonar/etiología , Masculino , Traumatismos del Cuello/diagnóstico , Traumatismos del Cuello/etiología , Respiración Artificial , Estudios Retrospectivos , Tráquea/cirugía , Resultado del TratamientoRESUMEN
INTRODUCTION: Acquired airway stenosis is a common complication in children after periods of tracheal intubation. We reviewed our experience in the endoscopic treatment of these lesions. PATIENTS AND METHODS: We performed a retrospective review of patients who presented acquired tracheal-subglottic stenosis (SGS) treated at our center from 2005 to 2012. We reviewed the etiology, age, clinical presentation, methods of diagnosis, number of bronchoscopies, angioplasty balloon dilations performed, and long-term results. RESULTS: A total of 18 patients (13 M, 5 F) were treated at our institution between 2005 and 2012. Median age at treatment was 3.5 months (range, 1-96 months). Of the 18 children, 16 children had SGS (all cases were postintubation), and 2 children presented tracheal stenosis (1 postintubation, 1 after tracheal surgery). Median intubation time was 30 days (range, 3-120 days). Extubation failure and stridor were the main clinical features. SGS were diagnosed as grade I in three patients, grade II in nine patients, and grade III in six patients. Bronchoscopy allowed diagnostic in all cases, and was followed by angioplasty balloon dilation, with a median of 2.5 (range, 1-5) sessions. In SGS grade I, the relation patient/number of dilations was 1; in SGS grade II 2.6, and in SGS grade III 3.5. Mitomycin was applied in 15 patients. No patients presented intraoperative complications or required reoperation. Median follow-up time was 36 months (range, 5-72 months) and no recurrence was noticed. CONCLUSIONS: Early endoscopic dilation with balloon shows as an effective and safe treatment in acquired tracheal and SGS.
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Angioplastia de Balón , Broncoscopía , Intervención Médica Temprana , Laringoestenosis/terapia , Mitomicina/administración & dosificación , Estenosis Traqueal/terapia , Niño , Preescolar , Terapia Combinada , Femenino , Humanos , Lactante , Recién Nacido , Intubación Intratraqueal/efectos adversos , Laringoestenosis/clasificación , Laringoestenosis/diagnóstico , Masculino , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/terapia , Retratamiento , Estenosis Traqueal/clasificación , Estenosis Traqueal/diagnósticoRESUMEN
To test the hypothesis that two modalities of IPC should decrease acute rejection and BT after SBTx in rats. Orthotopic allogenic SBTx was performed from Wistar to BN. IPC was performed by 2 ' and 5 ' superior mesenteric artery clamping, following 2-min and 5-min reperfusion before graft cooling and retrieving. Donor-recipient sets were randomly allocated to five groups: IPC2m4d, IPC2m7d, IPC5min7d, and the control groups for the two end points; ctrl4d and ctrl7d. IRI, rejection, and BT were assessed after four or seven days depending on the groups. Measured variables included: histology, leukocyte activation by tissue MPO determination, and proinflammatory cytokines (IL-b and TNF-α) to assess inflammatory response. Leukocyte activation was significantly reduced in IPC2m7d in comparison with Ctrl and IPC5min7d. Rejection tended to be lower in IPC2min7d. Cytokine levels were contradictory and not consistent with histology. Finally, BT was less frequent in IPC2min4d group but this benefit was missed in animals with rejection (7d). Inflammatory response (MPO) was reduced and rejection tended to be lower after in IPC2m7d. Bacterial translocation was reduced in IPC2min4d but the benefit was missed at day 7.
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Intestinos/trasplante , Precondicionamiento Isquémico , Animales , Traslocación Bacteriana , Citocinas/metabolismo , Supervivencia de Injerto , Inmunohistoquímica/métodos , Interleucina-1beta/sangre , Intestinos/patología , Arteria Mesentérica Superior/patología , Ratas , Ratas Wistar , Reproducibilidad de los Resultados , Factores de Tiempo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
PURPOSE: Graft-vs-host disease (GVHD) is a rare complication of transplantation of organs rich in immunocompetent cells. The goal of this study was to report the features of GVHD after small bowel transplantation (SBTx) in children. METHODS: The study involved a retrospective review of patients undergoing SBTx between 1999 and 2009 who had GVHD. RESULTS: Of 46 children receiving 52 intestinal grafts (2 liver-intestine and 3 multivisceral), 5 (10%) developed GVHD. Median age at transplant was 42 (19-204) months. Baseline immunosupression consisted of tacrolimus and steroids supplemented with thymoglobulin (n = 2) or basiliximab (n = 3) for induction. Median time between transplantation and GVHD was 47 (16-333) days. All patients had generalized rash, 2 had diarrhea, and 2 had respiratory symptoms. Other symptoms were glomerulonephritis (n = 1) and conjunctivitis (n = 1). Four developed severe hematologic disorders. The diagnosis was confirmed by skin biopsy in 4 patients and supported by chimerism studies in two. Colonoscopy and opthalmoscopic findings were also suggestive in one. Treatment consisted of steroids and decrease of tacrolimus, with partial response in four. Other immunosuppressants were used in refractory or recurrent cases. Three patients died within 4 months after diagnosis. CONCLUSION: Graft-vs-host disease is a devastating complication of SBTx, with high mortality probably associated with severe immunologic dysregulation.
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Enfermedad Injerto contra Huésped/etiología , Intestino Delgado/trasplante , Complicaciones Posoperatorias/etiología , Anticuerpos Monoclonales/uso terapéutico , Suero Antilinfocítico , Basiliximab , Niño , Preescolar , Quimerismo , Terapia Combinada , Femenino , Rechazo de Injerto/etiología , Rechazo de Injerto/inmunología , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Tolerancia Inmunológica , Inmunosupresores/uso terapéutico , Lactante , Intestino Delgado/inmunología , Masculino , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/mortalidad , Proteínas Recombinantes de Fusión/uso terapéutico , Estudios Retrospectivos , Tacrolimus/uso terapéutico , Resultado del TratamientoRESUMEN
Orthotopic liver transplantation is currently the treatment of choice in patients with end-stage liver disease for which no other therapy is available. In children, segmental liver transplantation with living donor, reduced-size cadaveric, and split cadaveric allografts has become an important therapeutic option. However, the resulting expansion of the donor pool has increased the risk for postoperative vascular and biliary complications, which affect children more frequently than adults. Early recognition of these complications requires radiologic evaluation because their clinical manifestations are frequently nonspecific and vary widely. Doppler ultrasonography (US) plays the leading role in the postoperative evaluation of pediatric patients. Current magnetic resonance (MR) imaging techniques, including MR angiography and MR cholangiography, may provide a wealth of pertinent information and should be used when findings at US are inconclusive. Computed tomography is a valuable complement to US in the evaluation of complications involving the hepatic parenchyma as well as extrahepatic sites and is commonly used to guide percutaneous aspiration and fluid collection drainage. Familiarity with and early recognition of the imaging appearances of the various postoperative complications of pediatric liver transplantation are crucial for graft and patient survival.
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Enfermedades de las Vías Biliares/diagnóstico , Diagnóstico por Imagen/métodos , Rechazo de Injerto/diagnóstico , Fallo Hepático/diagnóstico , Fallo Hepático/cirugía , Trasplante de Hígado/efectos adversos , Enfermedades Vasculares/diagnóstico , Enfermedades de las Vías Biliares/etiología , Niño , Preescolar , Rechazo de Injerto/etiología , Arteria Hepática/diagnóstico por imagen , Arteria Hepática/patología , Venas Hepáticas/diagnóstico por imagen , Venas Hepáticas/patología , Humanos , Lactante , Recién Nacido , Fallo Hepático/complicaciones , Trasplante de Hígado/diagnóstico por imagen , Trasplante de Hígado/patología , Pediatría/métodos , Radiografía , Cintigrafía , Ultrasonografía , Enfermedades Vasculares/etiologíaRESUMEN
BACKGROUND: Outcomes of split-liver transplantation (SLT) with pediatric donors have never been specifically reported. METHODS: A prospective multicenter study on SLT using donors younger than 15 years was conducted. Thirty-nine split-liver procedures generating a left lateral segment (LLS) and an extended right graft (ERG) were performed. In three cases, no recipient was found for ERG. In all but one case, the celiac trunk was maintained with LLS. Data were available for 67 grafts (90% of the total): 38 LLSs and 9 ERGs transplanted into 46 children and 20 ERGs transplanted into 20 adults. Sixty-two (93%) grafts were used for primary transplants and five (7%) for retransplantation. SLT were performed with 15 donors 10 years of age and less and with 24 between 11 and 15 years. RESULTS: Median follow-up was 24 months. Two-year patient and graft survival were 87% and 82%. Patient and graft survivals were not significantly different between pediatric and adult recipients, between recipients from donors 10 years of age and less and those between 11 and 15 years, and between recipients of LLS and ERG. Arterial complications occurred in 6% of cases (8% in the < or = 10 year donors group, 5% in the 11-15 year donors group). The incidence of other complications was similar between groups. CONCLUSIONS: SLT with pediatric donors, even younger than 10 years, provided results comparable with those achievable using adult donors. The similar incidence of arterial complications among patients receiving LLS or ERG suggests that maintenance of the celiac trunk with LLS is not detrimental for right-sided grafts.
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Hepatectomía/métodos , Trasplante de Hígado/métodos , Donantes de Tejidos/estadística & datos numéricos , Recolección de Tejidos y Órganos/métodos , Adolescente , Adulto , Niño , Preescolar , Femenino , Supervivencia de Injerto , Humanos , Lactante , Trasplante de Hígado/mortalidad , Trasplante de Hígado/fisiología , Masculino , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
We report the anaesthetic management of a 3-year-old-child with microvillus inclusion disease undergoing isolated small bowel transplantation. He required long-term total parenteral nutrition which was complicated with numerous episodes of catheter related sepsis. This resulted in thrombosis of the major blood vessels which critically restricted vascular access available for intravenous nutrition, becoming a life-threatening condition for the patient. Haemodynamic, respiratory parameters and urinary output were well preserved throughout the procedure. Besides a transitory increase in potassium following graft revascularization, biochemical changes were small. Anaesthetic management included comprehensive preoperative assessment, central venous angiography to depict accessibility of central and peripheral veins, assurance of additional vascular access through the intraoperative catheterization of the left renal vein, perioperative epidural analgesia and preservation of splanchnic perfusion to ensure implant viability.